Tranquilizers



r 2,987,544 1C6 Patented June 6, 1961 This invention relates to new derivatives of cyclopropylamine, More particularly, it is concerned with the cyclopropylamides of 3,4,5-trimethoxybenzoic acid and 3,4,5-trimethoxycinnamic acid, and a method for their preparation. The compounds of this invention are represented by the formula:

OHaO

QOONH CHsO and

These new compounds are made by reacting 3,4,5- trimethoxybenzoic acid or 3,4,5-trimethoxycinnamic acid or their reactive derivatives with cyclopropylamine. The reactive derivatives of 3,4,5-trimethoxybenzoic acid or 3,4,5-trimethoxycinna-mic acid are the corresponding easily dissociating esters, e.g., methyl 3,4,5-trimethoxybenzoate, ethyl 3,4,5-trimethoxycinnamoate and the like; or the corresponding acid halides, e.g., 3,4,5-trimethoxybenzoyl chloride, 3,4,5-trimethoxycinnamoyl bromide and the like. Among the reactions outlined above, those using 3,4,5-trimethoxybenzoyl chloride or 3,4,5-trimethoxy cinnamoyl chloride as the starting material give the best results.

In the preferred embodiment, the reaction between the acid chlorides and the cyclopropylamine is carried out in the presence of an acid acceptor, e.g., a trialkylamine such as triethylamine, a N,N-dialkylaniline such as dimethylaniline, an alkali carbonate such as sodium carbonate, an earth alkali bicarbonate such as calcium bicarbonate, and the like. Cyclopropylamine is also an operative acid acceptor; therefore, excess amounts of this amine can be present in the reaction medium.

The reaction may be performed in an inert diluent such as ether, acetone, ethylacetate, benzene, dimethylacetamide, or similar solvents. The term inert is used a to express that such a diluent is unreactive towards the reactant, the end product, and the acid acceptor where the latter is used. The reaction can be performed Within a temperature range of from about 20 C. or the freezing point of the diluent, whichever is higher, to about 50 C. or the boiling point of the solvent, whichever is lower. The most convenient and therefore preferred temperature range is from 0 C. to room temperature or 20 C.

The new compounds described have useful tranquilizing and muscle relaxing properties. Pharmacologically, such effects can be determined by observation of test animals for standard signs which depict such properties. Among such signs are muscle flaccidity of limbs, general body relaxation and the like. At lower doses, a tranquilizing drug afiects conditioned responses, secondary conditioned responses, and unconditioned responses in test animals. These responses are observed on animals which have learned a test routine consisting of being placed in a box, hearing a buzzer alarm which is followed by an electroshock. Trained animals escape the shock by jumping on a ledge as soon as put into the box (secondary response) or at least after the buzzer sounds (conditioned response). Under the influence of certain drugs, however, the animal does not jump because it no longer remembers the training, is phsyically unable to jump, or doesnt mind the punishing shock under the influence of the drug. With a tranquilizer secondary conditioned and conditioned responses can be observed at doses much lower than those necessary .for the observatin of the unconditioned response. The new drugs have, at low dosages, an unusual characteristic in that they block the secondary conditioned responses, the primary conditioned responses and the unconditioned responses; but unlike reserpine-like drugs, they do not result in deficiency of motor function and activity. In addition, the new drugs also have anticonvulsant properties.

The following illustrations are presented to teach the invention, but should not be construed as exclusive embodiments of the invention.

EXAMPLE 1 3,4,5-zrimethoxy-N-cyclopropylbenzamide To a solution of 5.7 g. (0.1 mole) of cyclopropylamine and 10.1 g. (0.1 mole) of triethylamine in 200 cc. of ether is added drop-wise 23.07 g. 0.1 mole) of 3,4,5-tri methoxybenzoyl chloride in 200 cc. of ether. Prior to the drop-wise addition, the solution is cooled in an ice bath and is then stirred mechanically throughout the addition. The reaction mixture is allowed to adjust to room temperature after the completion of addition and is stirred overnight although the reaction is almost instantaneous. The next day, the reaction mixture is filtered and the resulting solid is tritu-rated with Water to remove triethylamine hydrochloride. After drying, 24.2 g. of crude 3,4,S-trimethoxy-N-cyclopropylbenzamide is obtained which correspondents to 97% of theory. The new compound melts at 1478 C. and is recrystallized from cc. of methanol. It has an empirical formula of C H NO which calculates to 62.14% C, 6.82% H, 5.57% N and 25.47% 0. The analyzed values of the new compound are 62.08% C, 6.89% H, 5.53% N, and 25.38 0.

In a modification of this example, similar results are obtained by replacing triethylamine with additional cyclopropylamine. Thus, 1 mole of 3,4,5-trimethoxybenzoyl chloride is reacted with 2 moles of cycloproplamine.

EXAMPLE 2 3,4,5-trimethoxy-N-cycl0propylcinnamide A solution containing 8.2 g. (0.143 mole) of cyclopropylamine and 14.5 g. (0.143 mole) of triethylamine in 70 cc. of dimethylacetamide is cooled in an ice bath and stirred mechanically. To this solution is added dropwise 34.0 g. (0.143 mole) of crude 3,4,5-trimethoxycinnamoyl chloride dissolved in 70 cc. of dimethylacetamide. After stirring for about 45 minutes, the reaction mixture is diluted with water to about 5 times the existing volume and the resulting precipitate is filtered and dried. This product, 3,4,5-trimethoXy-N-cyclopropylcinnamide is recrystallized from a mixture of 200 cc. of methanol and 400 cc. of water. The melting point of the compound is 168-9 C. and it is obtained in a yield of 88% or 33 g. The known compound has the empirical formula C H NO of which the calculated values are 64.96% C, 6.91% H, 5.05% N, and 23.8% 0. The analytical values are 65.09% C, 6.98% H, 4.95% N and 23.03% 0. I

3 EXAMPLE 3 In a modification of Example 2, the identical procedure is followed with the exception of using 3,4,5-trimethoxybenzoyl chloride in place of crude 3,4,5-trimethoxycinnamoyl chloride. After working up, 3,4,5-trimethoxy-N- cyclopropylbenzamide is obtained in a yield of 88%, melting at 147-8 C. after recrystallizing from 33% aqueous ethanol by volume.

EXAMPLE 4 In a modification of Example 1, the identical procedure is used with the exception of using 3,4,5-trimethoxycinnamoyl chloride in place of 3,4,5-trimethoxybenzoyl chloride in an equimolar amount. 3,4,5-trimethoxycinnamide is obtained in a yield of 88%, melting at 1689 C. after recrystallization from 33% aqueous methanol by volume.

The acid chlorides used in the above examples, namely the 3,4,5-trimethoxybenzoyl chloride and the 3,4,5-trimethoxycinnamoyl chloride are made by refluxing the corresponding acids with an excess of thionyl chloride. The excess thionyl chloride is then distilled OE and the last traces thereof are removed by adding a small amount of benzene, distilling oil the benzene, re-adding some benzene and re-distilling until all traces of benzene have boiled over. The cooled, crude acid chlorides thus obtained may be used without further purification. They, can, however, be recrystallized from acetone/pentane, benzene/pentane, and similar solvent mixtures. Thionyl chloride can also be replaced by phosphoroxychloride or phosphorouspentachloride to prepare 3,4,5-trimethoxybenzoyl chloride or 3,4,5-trimethoxycinnamoyl chloride according to known methods.

The reaction between the trimethoxybenzoyl chloride and cyclopropylamine or the correspondingreaction between 3,4,5-trimethoxycinnamoyl chloride and cyclopropylamine is exothermic, and when operating in small batches, the reaction vessel should be cooled or fitted with a condensing unit to avoid loss of low boiling cyclopropylamine or solvent. The excessive exothermicity of the reaction accounts for the almost instantaneous reaction that takes place. Due to this high reaction rate, the above exemplified reactions may also be used in continuous operations.

EXAMPLE 5 3,4,5-trimethoxy-N-cyclopropylbenzamide A 5% suspension of 3,4,5-trimethoxy-N-cyclopropylbenzamide in water is made under sterile conditions. Several groups of mice are injected intraperitoneally with this solution at various dosages to establish the acute toxicities. In this manner, an LD of 750 mg./kg. is established. Other groups of mice are given the above 5% solution orally by forced feeding. An oral LD of 1500 mg./kg. is observed. The term LD is recognized to mean that the given dosage is fatal to one-half of the animals so tested.

A similar acute toxicity study of 3,4,5-trimethoxy-N- cyclopropylbenzamide in rats leads to the same LD values as obtained in mice.

In the rats, the tranquilizing efiect begins at an oral dose of about 150 mg./kg. by blocking the conditioned and secondary condition response of the test animals, while the unconditioned response remains normal. At a dose of 400 mg./kg., the unconditioned response is also blocked, but the rats behave normally in all other respects.

The same signs can be demonstrated after an intraperitoneal dose, but only one-half of the oral dose is required.

EXAMPLE 6 3,4,S-trimethoxyN-cycl0pr0pylcinnamide The procedure in Example 5 is repeated in mice and rats with a five percent suspension of 3,4,5-trimethoxy-N- cyclopropylcinnarnide. An oral LD of 750 mg./kg. in rats and mice and an intraperitoneal LD of 500 rug/kg. in mice is established.

At an oral dose of 250 mg./kg., the secondary condi tioned, conditioned and unconditioned responses are all blocked in the rats but without any impairment of motor functions and activities in test species.

An intraperitoneal dose of rug/kg. is found to block the secondary conditioned and conditioned responses, without affecting the unconditioned responses or any other function of the rats.

By testing this compound in some higher animals, it is found that the blood pressure'in cats is slightly lowered. In dogs the compound is found to have an effect similar to that seen with known tranquilizers and lasting between 24 and 48 hours when a single dose of between 25 and 300 mg./kg. is administered orally.

Others may practice the invention in any of the numerous Ways which Will be suggested to one skilled in the art by the present disclosure. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

I claim:

1. 3,4,S-trimethoxy-N-cyclopropylbenzamide.

2. 3,4,S-trimethoxy-N-cyclopropylcinnamide.

References Cited in the file of this patent UNITED STATES PATENTS 1,939,496 Guggenheim Dec. 12, 1933 2,870,145 Perron Jan. 20, 1959 v FOREIGN PATENTS 403,892. Great Britain Ian. 4, 1934 663,903 Great Britain Dec. 27, 1951 

1. 3,4,5-TRIMETHOXY-N-CYCLOPROPYLBENZAMIDE.
 2. 3,4,5-TRIMETHOXY-N-CYCLOPROPYLCINNAMIDE. 